This SPORE intends to build on M. D. Anderson's deep tradition of translational research and discovery in head and neck (HN) cancer therapy and chemoprevention to improve the basic understanding and clinical control of HN cancer. In response to our previous review, this revised application includes a new project, Project 1 (Intrinsic Apoptosis Phenotype and Susceptibility to Squamous Cell Carcinoma of the Oral Cavity), a significantly revised project (Project 3, previously numbered Project 2, Predictors of Resistance to Dual VEGFR/EGFR Targeted Therapy of Head and Neck Cancer) and two projects that were previously well-reviewed, Cancer Risk Assessment in Patients with Oral Premalignant Lesions: An Integrative Approach (now numbered as Project 2), and Targeting EGFR and the IGF Axis for Therapy of Head and Neck Squamous Cell Carcinoma (Project 4). We will investigate associations between genetic variants, apoptotic capacity phenotypes, and oral cancer risk (Project 1). We will assess the host susceptibility, global and specific molecular aberrations in oral premalignant lesions and epidemiologic factors build a model of risk for oral carcinogenesis (Project 2). We will investigate novel molecular profiling methods to identify signatures associated with resistance to an agent that co-targeting EGFR and VEGFR (Project 3), and we will investigate co-targeting EGFR and insulin-like growth factor 1 receptor (IGF-1R) (Project 4) in order to improve on the clinical benefit already achieved by EGFR inhibitors (e.g., cetuximab) in HN cancer patients. The translational expertise/resources of our biostatistics (e.g., comprehensive methodologies and models for assessing multiple biomarkers) and pathology cores (e.g., cutting-edge tissue banking) are unsurpassed in the world. The past trial activation and accrual record of this HN SPORE was the appropriate target of criticism in our previous review; thus, the SPORE leadership team has implemented several mechanisms to enhance the oversight, and thus activation and accrual, of our SPORE clinical trials, as detailed throughout this revised application. M. D. Anderson Cancer Center has reaffirmed its extraordinary commitment to this SPORE renewal. SPORE PI Dr. Lippman led a rigorous review of previous SPORE projects and relevant new science as we designed, refined, and selected projects for this revised renewal application. With substantive changes made to our application and the strengths of an exceptional leadership team and outstanding resources, we believe this HN SPORE application now reflects the most exceptional constellation of SPORE components and investigators that we could propose.